endocrine system disorders and drugs. definititions endocrine: secretes into blood exocrine:...
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Endocrine System
Disorders and Drugs
Definititions
• Endocrine: secretes into blood
• Exocrine: secretes into epithelial surfaces
• Hormone: product secreted by endocrine gland– Autocrine: affects cell that secreted it– Paracrine: affects nearby cells
Endocrine Organs
• Hypothalamus• Pituitary• Pineal• Thyroid• Parathyroid• Thymus• Adrenals
• Pancreatic Islets• Ovaries• Testes• Other
– Heart– Kidneys– Endothelium
Mechanisms of Hormonal Control
• Rhythms of Release– Diurnal, Pulsatile-cyclical, Substrate level
• Feedback systems: +,-
• Act only on cells with appropriate receptors—alter cell action/metabolism
• Elimination: kidneys excrete or liver metabolizes
• Under control of nervous system, but in turn influence nervous system
Hormone Structural Classes
• Water Soluble– Peptides– Glycoproteins– Polypeptides– Amines
• Lipid soluble– Steroids (cholesterol derivatives)– Arachidonic derivatives
Hormone Transport
• Targets– Autocrine – affect cell that released hormone– Paracrine – affect nearby cells– Endocrine – affect distant cells
• Transport– Water soluble travel unbound– Lipid soluble are mostly bound to carrier
proteins
Hormonal Mechanisms of Action
• Receptors:– Location: Surface (membrane), Internal– Affinity
• Activation effects– Change membrane permeability by affecting
existing channel proteins– Activate existing proteins via second
messenger– Stimulate synthesis of new proteins
Thyroid
• Two thyroid hormones– T4 (thyroxine), T3– Must have iodine to synthesize
• Effects– Stimulation of energy use (Na/K pump)
• ↑O2 use, higher body temp
– Stimulation of heart• ↑HR, ↑contraction
– Promotion of growth and development• Maturation of nervous and muscle tissue
Fate of Thyroid Hormones
• Fate of thyroid hormones– More T4 released than T3– T4 is converted to T3 by enzymes in
peripheral tissues– 99.5% of both are bound to plasma proteins
• Hepatic metabolism
• Half-life– T3: 1.5 days– T4: 7 days
Regulation of Thyroid Hormone
• Hypothalamus – TRH
• Stimulates:
• Anterior Pituitary – TSH
• Stimulates:
• Thyroid: T3, T4
• Inhibits:
• Anterior -TSH
Influence of Iodine
• Not enough iodine– Thyroid enlarges: goiter– Increases ability to absorb iodine– Compensation may be enough to keep T4, T3
at normal levels
• Too much iodine– Thyroid decreases iodine uptake– Decreased T4, T3 release
Hypothyroidism
• Mild adult: hypothyroidism
• Sever adult: myxedema
• Infancy: cretinism
Adult Hypothyroidism• Etiology
– Thyroid malfunction• Chronic autoimmune thyroiditis (Hashimoto’s dz)• Insufficient Iodine• Surgical removal or radioactive iodine tx• Insufficient TSH or TRH
• Clinical Manifestations– Face: pale, puffy, expressionless
– Skin: cold and dry
– Hair Brittle, alopecia
– Heart rate, Body temperature
– Lethargy, depression, fatigue, cold intolerance
Hypothyroidism
• Laboratory monitoring– TSH– T4– T3
• Treatment– T4 replacement
• Levothyroxine (T4)• Levothyroxine plus liothyronine (T3)
Hypothyroid in Infants
• Mental retardation
• Large protruding tongue, potbelly, dwarfish posture
• Abnormal development of:– Nervous system– Bones, teeth,– Muscles
• Early treatment (2-3 days): normal
• Delayed tx: (2-3 months): physical normal, but mental damage is done
Maternal Hypothyroidism
• Can cause decreased IQ and other neuro problems
• Fetal thyroid gland is fully functional by second trimester
• First trimester is critical
• Screening for all pregnant women
Hyperthyroidism
• Two forms:– Grave’s Disease: exophthalmos– Plummer’s Disease (toxic nodular goiter)
• Thyrotoxicosis– Heart: Tachy, dysrhythmias, angina– Rapid thought, speech– Nervousness, insomnia– Muscle weakness and/or atrophy– Increased appetite, weight loss
Grave’s Disease
• 6 times more likely in women; ages 20 – 40
• Thyroid stimulating immunoglobulins
• Treatment– Surgical removal of thyroid tissue– Destruction of thyroid tissue with radioactive
iodine– Suppression of thyroid hormone synthesis– Adjunct treatment: propanolol and iodine
Hyperthyroid
• Toxic nodular Goiter: thyroid adenoma– Same treatment as grave’s Disease
• Thyrotoxic Crisis (Thyroid storm)– Manifestations:
• Hyperthermia• Severe tachycardia• Profound weaknes• Unconsciousness, coma, heart failure
– Etiology: overdose or excess endogenous production
Thyroid Function Tests
• TSH– More sensitive– Can help to distinguish primary problems from
secondary
• T4, Free T4
• T3
Levothyroxine
• Synthroid, Levothroid, Levoxyl
• Pharmacokinetics– Absorbed in GI tract– Converted to T3 in blood and tissues– Half-life
• Takes four weeks to reach steady state• Convenient daily dosing
• Adverse effects– Thyrotoxicosis
Levothyroxine Interactions
• Drugs that reduce levothyroxine:– Cholestyramine, Colestipol, Calcium,
Sucralfate, Aluminum antacids, Iron suppl.
• Drugs that help break down levothyroxine– Phenytoin, carbamazepine, rifampin,
sertaline, phenobarbital
• Levothyroxine potentiates:– Warfarin– Catecholamines (epinephrine, et al.)
Levothryoxine
• Almost always PO
• May be given IV if necessary
• Evaluation– TSH and T4 levels– Symptoms
• Duration of Therapy– LIFELONG!!!
Hyperthyroid Medications
• Propylthiouracil (PTU) & Methimazole– Inhibits thyroxine production
• Radioactive Iodine-131– Taken up by thyroid where it decays and
destroys thyroid cells– Half-life 8 days– Reduction is gradual: effects begin at 2-3
weeks and increase up to 2-3 months– 66% of patients cured by one dose
Radioactive Iodine
• Benefits:– Cheap– No surgery or recovery– Death unlikely– Only thyroid is affected
• Drawbacks– Delayed effects– Delayed hypothyroidism (10% in first year)
Pituitary
• Growth Hormone (GH)– Too much: gigantism, acromegaly
• Surgical removal or medical suppression
– Too little: dwarfism: treat with GH• Two forms: somatotropin and somatrem• Adverse effects:
– Hyperglycemia– Hypothyroidism– Antibody development– Are impaired by glucocorticoids
Pituitary
• Prolactin Excess:– Etiology
• Pituitary adenoma• Hypothalamic injury• Drugs,• Idiopathic
– Manifestations• Women, amenorrhea, galactorrhea, infertility• Men: decreased libido and potency, galactorrhea• Delayed puberty
Antiduretic Hormone
• AKA Vasopressin or AVP (argenine vasopressin)
• Actions– ↑ water reabsorption in renal collecting ducts– Vasoconstriction of vascular smooth muscle
and GI tract smooth muscle
• Not enough: Diabetes insipidus
• Too much: SIADH
Adrenal Glands
• Cortex: secretes steroids generally called corticosteroids:– Mineralocorticoids– Glucocorticoids– Androgens (male sex hormones)
• Medulla– Nervous tissue– Secretes epinephrine and norepinephrine
Glucocorticoids
• Several produced– Cortisol is main one (amount and effect)
• Physiologic effects– Low levels
• Pharmocologic effects– High levels
Glucocorticoids
• Physiological effects– Carbohydrate metabolism
• Gluconeogenesis• Reduction of peripheral glucose use• Promotion of glycogen formation
– Protein catabolism – Fat catabolism– Cardiovascular: membrane permeability, RBC
counts, ↑polys, lymphs and monos
Glucocorticoids
• Physiologic effects cont– Skeletal muscle – maintain perfusion– CNS: affect excitability
• Too little: depression, lethargy, irritability• Too much: excitation, euphoria
– Stress: in combination with epinephrine, ensure that glucose and blood supply is adequate
– Respiratory in neonates: stimulates maturation of lung
Regulation of Glucocorticoids
• Hypothalamus: CRF
• Stimulates Anterior Pituitary: ACTH
• Stimulates Adrenal Cortex: Synthesize and release glucocorticoids
• Glucorticoids suppress hypothalamus and pituitary release of CRF and ACTH
• Two modes of stimulation– Circadian rhythm– Stress
Other Cortical Steroids
• Mineralocorticoids– Most important is aldosterone– Controlled by RAAS
• Adrenal androgens– Men: not much effect, testosterone from
testes is greater– Women: testosterone is metabolized from
androgens. Causes axillary & pubic hair and maintains libido
Glucorticoid Disorders
• Glucocorticoid excess: Cushing’s Syndrome– Etiology
• Excess ACTH (Cushing’s Disease)
• Hypersecretion by adrenal adenoma or carcinoma
• Large doses of exogenous glucocorticoids
– Manifestation• Obesity, hyperlgycemia, glycosuria, hypertension,
F&E imbalances, osteoporosis, muscle weakness, hirsutism, increased infections
• Weakened skin, striae• Fat redistribution: belly, moon face, buffalo hump
Glucorticoid Disorders
• Glucocorticoid deficit: Addison’s Disease– Manifestations
• Weakness, emaciation, hypglycemia, hyperpigmentation, F&E imbalances
– Treatment• Glucocorticoid replacement
• Acute adrenal Insufficiency (Adrenal Crisis)– Adrenal failure, pituitary failure, sudden d/c of
exogenous glucocorticioids
– Hypotension, dehydration, weakness, lethargy, NVD, shock, death
Glucocorticoid Therapy
• Hydrocortisone: artificial cortisol– Has both gluco- and mineralocorticoid
properties– IV or IM
• Cortisone converts to hydrocortisone in body– PO or IM
• Inhibitors of corticosteroid synthesis– Ketoconazole– Aminoglutethimide
Glucocorticoids used for non-Endocrine purposes
• Pharmacologic Actions– Anti-inflammatory and Immune effects
• Inhibit prostaglandin, leukotriene, and histamine synthesis
• Suppress infiltration of phagocytes• Suppress proliferation of lymphocytes
– Effects on Metabolism and Electrolytes• Glucose levels rise• Protein synthesis suppressed• Fat deposits mobilized• Fewer electrolyte effects, but can inhibit calcium
absorption
Therapeutic Uses
• Rheumatoid Arthritis• SLE• Inflammatory Bowel Disease (IBD)• Miscellaneous Inflammatory D/Os• Allergic conditions (not acute anaphylaxis)• Asthma• Dermatologic disorders• Neoplams• Transplant rejection• Preterm infant
Glucorticoids Adverse Effects
• Adrenal insufficiency
• Osteoporosis: long term therapy
• Infection
• Glucose intolerance
• Myopathy
• F&E disturbance
• Growth retardation
• Psychological disturbances
Glucorticoids Adverse Effects
• Cataracts and Glaucoma
• Peptic Ulcer Disease
• Iatrogenic Cushing’s Disease
• Ischemic Necrosis – especially caution with ETOH
Agents
• Short Acting Anti-inflammat– Cortisone, Hydrocortisone 1
• Intermediate Acting– Prednisone 4– Prednisolone 4– Methylprednisolone 5– Triamcinolone 5
• Long acting– Betamethasone 20-30– Dexamethasone 20-30